There remains a critical unmet need to develop novel therapeutic strategies for the treatment of MDD with more rapid onset of action, higher rates of response and remission for both depressed mood and anhedonic symptoms as well as diminished side-effect profiles. In studies reported by our group and others, the metabotropic glutamate receptor subtype 5 (mGlus) has been shown to function as a close signaling partner with NMDARs and may provide key regulation of NMDAR functions in limbic regions thought to be disrupted in individuals with MDD and anxiety disorders, and through a combination of genefic and pharmacological studies has emerged as an exciting new molecular target for MDD. Therefore, we aim to test the hypothesis that selective antagonism of mGlus may result in rapid and robust efficacy for the treatment of symptoms associated with MDD. We have discovered of a highly selective series of biaryl ether mGIUs KlAMs, exemplified by VU0409106 and VU0431316, provide an exciting opportunity to assess whether selective antagonism of mGIUs can provide an alternative approach to NMDAR antagonists and other clinical available antidepressants for the treatment of symptoms associated with MDD. However, we will need to develop additional novel mGlus NAMs with new intellectual property (IP) position as second generation preclinical candidates (PCCs) and back-up compounds. Thus, we will further optimize the biaryl ether series of mGlus NAMs, incorporating two points of structural diversity, divergent from VU0409106 and VU0431316, to afford IP position through the application of an iterative parallel synthesis and screening strategy (the Technology Enabled Synthesis or TES approach), as well as to ensure novel ligands maintain affinity at the MPEP site. In parallel, we will further optimize the DMPK profile of our new mGlus NAMs, relative to VU0409106 and VU0431316, to afford PCCs and back-ups with balanced profiles suitable to validate mGlus NAMs in preclinical models of depression and to initiate IND-enabling studies.